Rational Antimicrobial

Therapy
Rianto Setiabudy &
Dewi Selvina Rosdiana
Department of Pharmacology FMUI
Lecture for Infection and Immunology Module
April, 2012

1
 Introduction (1)
The problems we are facing:
The ever increasing problem of bacterial
resistance (MRSA, VRE, ESBL producing
pathogens, MDR hospital pathogens)
Spread of infections in hospital setting
Cost of treatment
Inappropriate use of antimicrobial agents

2
 Introduction (2)
Lack of new antimicrobial agents
developed in recent years
Unnecessary financial burden to the
patients
Scarcity of objective information on
appropriate use of antimicrobial agents

3
 Outlines (1)
Pharmacological factors affecting
tissue penetration of antimicrobial
Selecting an appropriate antimicrobial
agent
Use of combinations
Prophylaxis
Duration of antimicrobial treatment

4
 Outlines (2)

Patterns of antimicrobial killing

activity
Penetration of antimicrobials into
CSF
Factors responsible for treatment
failure

5
Pharmacologic factors affecting tissue
penetration of antimicrobials

Antimicrobial concentration in blood

Molecular size of antimicrobials
Protein binding
Lipid solubility
Ionic charge
Binding to exudate or tissue
Presence of inflammation
Active transport mechanism
Pathway of excretion
6
Selecting an antimicrobial agent
clinical signs & symptoms

clinical diagnosis

Educated guess or
Culture and sensitivity test

etiological diagnosis

determine the drug of choice

7
Selecting an antimicrobial agent (contd)
determine the drug of choice
If in appropriate give a second-
line drug. Consider: safety,
efficacy, suitability, and cost

give the drug

evaluate the result

stop or continue or modify

the treatment as necessary
8
Tips for selecting an appropriate
antimicrobial agent (1)
If a sensitivity test indicates that a pathogen is
sensitive to some antibiotics, it does not mean
all these agents have equal clinical efficacy
If two or more antibiotics are equally safe and
effective, choose the one with narrower
antibacterial spectrum
In life-threatening condition a de-escalating
therapy may be applied if the etiology is
unknown
Generic antibiotics are not of low quality but
their price is much more affordable

9
Tips for selecting an appripriate
antimicrobial agent (2)
A new generation antibiotic is not always
superior to its older generations
A slightly more potent antibiotic shown in
vitro, is not necessarily associated with better
clinical efficacy

10
 Use of antimicrobial combinations
(1)
Indications:
Empirical therapy of severe infections in
which cause is unknown
Treatment of polymicrobial infections
Enhancement of antimicrobial activity in
treatment of specific infections
Prevention of emergence of resistance

11
Use of antimicrobial combinations
(2)

Examples of appropriate use of AM combinations:

Septic shock due to Gram negative pathogens
Life-threatening infection of undetermined cause
Enterococcal endocarditis
Serious infections due to P. aeruginosa
Intra-abdominal infection
Tuberculosis and leprosy treatment

12
 Use of antimicrobial combinations
(3)
Disadvantages of AM combinations:
Increased risk of toxicity
Selection of multiple-drug-resistant
microorganisms
Increased cost
Possibility of unexpected antagonistic
effect

13
Use of antimicrobial combinations
(4)

Examples of possible clinical antagonistic

effect:
Lepper & Dowling (Arch Int Med
1951;88:489-94)
Pneumococcal meningitis treated with:
Penicillin alone: fatality rate = 21%
Penicillin + chlortetracycline: fatality rate =
79%

14
 Prophylaxis
Characteristics of successful prophylaxis:
Aimed at a specific pathogen
The pathogen is highly sensitive to the
prophylactic agent used
Characteristics of unsuccessful
prophylaxis:
Aimed at any or all microorganism in the
environment of a patient
(Chambers, 2001)

15
 Duration of therapy (1)
Determined by:
The ability of the pathogens to resist
hosts defense mechanism
Physical location of the pathogen
Potency of the AM agent
The frequency of development of
resistance

16
 Duration of therapy (2)
Examples:
Acute uncomplicated cystitis: one dose 3
days
Acute gonococcal urethritis: one dose
Pneumococcal pneumonia: until afebrile 3
days, at least 5 days
Bacterial endocarditis: 4 weeks
Streptococcal pharyngitis: 10 days
Pulmonary tuberculosis: 6 months
Extra pulmonary tuberculosis: 12-24 months

17
Factors causing failure of treatment (1)

Poor antibacterial activity of a drug

Wrong route of administration or
wrong dosage
The location of infection is
inaccessible by the antimicrobial
agent
Poor hosts defense mechanism
Premature discontinuation of
treatment
18
Factors causing failure of treatment (2)

Serious toxicity necessitates

discontinuation of therapy
Resistance of the microorganism
Superinfection
Foreign body or necrotic tissues
Patients incompliance

19
Time-kill curves of P. aeruginosa
with exposure to tobramycin
Log CFU/ml

Time (h)
(Craig, 1991)
20
Patterns of antibiotic killing activity
(1)

Pattern 1: concentration-dependent
killing
E.g.: aminoglycosides,
fluoroquinolones
Strategy of dosing regimen:
maximize concentrations
Parameters determining efficacy:
ratios of Cmax/MIC or AUC/MIC
(Deziel-Evans, 1986)
21
Time-kill curves of P. aeruginosa with
exposure to ticarcillin
Log CFU/ml

Time (h)
(Craig, 1991)
22
Patterns of antibiotic killing activity
(2)

Pattern 2: time-dependent killing

E.g.: betalactams, macrolides,
oxazolidinedinones
Strategy of dosing regimen: maximize
duration of exposure to antibiotics
Parameters determining efficacy:
length of time of above-MIC antibiotic
blood level
23
 Pharmacokinetic/Pharmaco-
dynamic (PK/PD) parameters

For concentration-dependent killing

pattern:
AUC/MIC (required: 125 and 30
for Gram negative and Gram positive
pathogens, respectively )
Cmax/MIC (required: 10)
For time-dependent killing pattern:
Time above MIC (required: 40%)
24
 Pharmacokinetics and pharmaco-dynamics
of antimicrobial agents

CONC. Cmax AUC/MIC

Cmax/MIC
Time above MIC
Area Under
the Curve

MIC

Time
Time above-MIC 25
Penetration of antimicrobials into
cerebrospinal fluid (1)
Excellent:
Trimethoprim
Sulfonamides
Chloramphenicol
INH
Rifampicin
Flucytocin
26
Penetration of antimicrobials into
cerebrospinal fluid (2)

Good with inflammed meninges:

Penicillin G
Ampicillin
Cloxacillin
Ticarcillin
Piperacillin

27
Penetration of antimicrobials into
cerebrospinal fluid (3)

Ceftriaxone
Ceftazidime
Aztreonam
Imipenem
Fluoroquinolones

28
 Penetration of antimicrobials into
cerebrospinal fluid (4)
Poor penetration:
Aminoglycosides
First generation cephalosporins
Clindamycin
Vancomycin
Cefoxitin

29
Factors responsible for treatment
failure (1)
Poor antimicrobial activity
Active antimicrobial agent fails to be
delivered to the site of infection in
sufficient concentration
Inaccessible site of infection
Inadequate host body defenses
Treatment duration is too short to
prevent relapse
30
Factors responsible for treatment
failure (2)

Serious toxicity necessitates

discontinuation of therapy
Development of resistance
Superinfection occurred
Foreign body or necrotic tissues
Patients incompliance

31
THANK YOU

32